Omega-3 fatty acids reverse age-related decreases in nuclear receptors and increase neurogenesis in old rats

Neuroscience Centre, ICMS, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary University of London, Whitechapel, London, United Kingdom.
Journal of Neuroscience Research (Impact Factor: 2.59). 08/2010; 88(10):2091-102. DOI: 10.1002/jnr.22390
Source: PubMed


Retinoic acid receptors (RARs), retinoid X receptors (RXRs), and peroxisome proliferator-activated receptors (PPARs) are transcription factors involved in many cellular processes, such as learning and memory. RAR and RXR mRNA levels decrease with ageing, and the decreases can be reversed by retinoic acid treatment, which also alleviates age-related memory deficits. The omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have neuroprotective effects in the aged brain and are endogenous ligands of RXR and PPAR. We investigated whether dietary EPA and DHA supplementation reverses age-related declines in protein levels of these receptors in rat forebrain. Two studies were conducted comparing adult and old rats. In the first, old rats were fed standard or EPA/DHA-enriched (270 mg/kg/day, EPA to DHA ratio 1.5:1) diets for 12 weeks. Analysis by Western blot revealed significant decreases in RARalpha, RXRalpha, RXRbeta, and PPARgamma in the forebrain with ageing, which were reversed by supplementation. Immunohistochemical analysis of the hippocampus showed significant age-related decreases in RARalpha and RXRbeta expression in CA1 and the dentate gyrus, which were restored by supplementation. Decreases in hippocampal doublecortin expression were also partially alleviated, suggesting a positive effect on neurogenesis. We also investigated the effects of DHA supplementation (300 mg/kg/day for 12 weeks) on RARalpha, RXRalpha, and RXRbeta expression in the prefrontal cortex, striatum, and hippocampus. Overall, DHA supplementation appeared to increase receptor expression compared with the untreated old group. These observations illustrate additional mechanisms that might underlie the neuroprotective effects of omega-3 fatty acids in ageing.

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Available from: Simon C Dyall, Oct 14, 2014
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    • "Many women now use alternative therapies for postmenopausal health including dietary soy and isoflavone supplements instead of, or in addition to, traditional hormone therapy (Newton et al., 2002; Kurzer, 2003). Moreover, n − 3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been suggested as being involved in the development and maintenance of learning memory performance (Gamoh et al., 1999; Hashimoto et al., 2009a, 2011; Dyall et al., 2010; Boucher et al., 2011). The n− 3 PUFAs ameliorated endothelial dysfunction in diabetic rats (Matsumoto et al., 2009), and led to attenuation of the contractile responses of isolated resistance arteries (MacLeod et al., 1994). "
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    ABSTRACT: Aims To investigate effects of n-3 polyunsaturated fatty acids on cerebral circulation, ovariectomized (OVX) rats were administered phospholipids in krill oil (KPL) or triglycerides in fish oil (FTG); effects on the Ca2 + regulating system in their basilar artery (BA) were then analyzed. Main methods The rats were divided into 4 groups: control, OVX, OVX given KPL (OVXP), and OVX given FTG (OVXT) orally, daily for 2 weeks. Time dependent relaxation (TDR) of contractile response to 5HT in BA was determined myographically, Na+/Ca2 + exchanger (NCX) 1 mRNA expression was determined by real time PCR, and nucleotides were analyzed by HPLC. Key findings The level of TDR in OVX that was significantly lower than in the control, was inhibited by L-NAME and indomethacin; TEA inhibited TDR totally in the control but only partly in OVXP and OVXT. Relaxation induced by the addition of 5 mM of KCl to the BA pre-contracted with 5-HT was inhibited by TEA in the controls, OVXP and OVXT, but not in OVX. Overexpression of NCX1 mRNA in the BA from OVX was significantly inhibited by FTG. The ratio of ADP/ATP in cerebral arteries from OVX was significantly inhibited by KPL and FTG. Levels of triglyceride and arachidonic acid in the plasma of OVX increased, but were significantly inhibited by KPL and FTG. Significance Ovarian dysfunction affects Ca2 + activated-, ATP-sensitive- K+ channels and NCX1, which play crucial roles in the autoregulation of cerebral blood flow. Also, KPL may become as good a supplement as FTG for postmenopausal women.
    Life sciences 03/2014; 100(1). DOI:10.1016/j.lfs.2014.01.070 · 2.70 Impact Factor
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    • "It has been shown that the hippocampal expression of retinoic receptors is a good indicator of vitamin A status and intracellular availability of RA. Indeed, several studies have demonstrated age-related decreases in mRNA expression or protein levels of retinoid receptors in mice and rat brain (Enderlin et al., 1997; Etchamendy et al., 2001; Feart et al., 2005; Mingaud et al., 2008; Dyall et al., 2010) indicating a decreased bioavailability of the ligand. More specifically, age-induced decreased RARβ in the whole brain has been associated with memory deficits and all these effects can be normalized by RA treatment (Etchamendy et al., 2001). "
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    ABSTRACT: It is now established that vitamin A and its derivatives, retinoic acid (RA), are required for cognitive functions in adulthood. RA hyposignaling and hyperactivity of glucocorticoid (GC) pathway appear concomitantly during aging and would contribute to the deterioration of hippocampal synaptic plasticity and functions. Furthermore, recent data have evidenced counteracting effects of retinoids on GC signaling pathway. In the present study, we addressed the following issue: whether the stimulation of RA pathway could modulate intrahippocampal corticosterone (CORT) levels in middle-aged mice and thereby impact on hippocampal plasticity and cognitive functions. We firstly investigated the effects of vitamin A supplementation and RA treatment in middle-aged mice, on contextual serial discrimination task, a paradigm which allows the detection of early signs of age-related hippocampal-dependent memory dysfunction. We then measured intrahippocampal CORT concentrations by microdialysis before and after a novelty-induced stress. Our results show that both RA treatment and vitamin A supplementation improve "episodic-like" memory in middle-aged mice but RA treatment appears to be more efficient. Moreover, we show that the beneficial effect of RA on memory is associated to an increase in hippocampal PSD-95 expression. In addition, intrahippocampal CORT levels are reduced after novelty-induced stress in RA-treated animals. This effect cannot be related to a modulation of hippocampal 11β-HSD1 expression. Interestingly, RA treatment induces a modulation of RA receptors RARα and RARβ expression in middle-aged mice, a finding which has been correlated with the amplitude of intrahippocampal CORT levels after novelty-induced stress. Taken together, our results suggest that the preventive action of RA treatment on age-related memory deficits in middle-aged mice could be, at least in part, due to an inhibitory effect of retinoids on GC activity.
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    ABSTRACT: Many clinical and animal studies demonstrate the importance of long-chain polyunsaturated fatty acids (LCPUFA) in neural development and neurodegeneration. This review will focus on involvement of LCPUFA from genesis to senescence. The LCPUFA docosahexaenoic acid and arachidonic acid are important components of neuronal membranes, while eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid also affect cardiovascular health and inflammation. In neural development, LCPUFA deficiency can lead to severe disorders like schizophrenia and attention deficit hyperactivity disorder. Perinatal LCPUFA supplementation demonstrated beneficial effects in neural development in humans and rodents resulting in improved cognition and sensorimotor integration. In normal aging, the effect of LCPUFA on prevention of cognitive impairment will be discussed. LCPUFA are important for neuronal membrane integrity and function, and also contribute in prevention of brain hypoperfusion. Cerebral perfusion can be compromised as result of obesity, cerebrovascular disease, hypertension, or diabetes mellitus type 2. Last, we will focus on the role of LCPUFA in most common neurodegenerative diseases like Alzheimer’s disease and Parkinson’s Disease. These disorders are characterized by impaired cognition and connectivity and both clinical and animal supplementation studies have shown the potential of LCPUFA to decrease neurodegeneration and inflammation. This review shows that LCPUFA are essential throughout life.
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